Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease

Grixti, Justine M.; Theron, Chrispian W.; Salcedo-Sora, J. Enrique; Pretorius, Etheresia; Kell, Douglas B.

doi:10.1101/2024.04.06.588397

Cited by 5 publications

(1 citation statement)

References 315 publications

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“…Since the acceptance of this article, three significant papers on fibrinaloid microclots have been published. One [429] describes the importance of microclots in intensive care unit morbidity and disseminated intravascular coagulation, while two others describe an automated microscope method for the detection of microclots [430,431] and their degradation by nattokinase [431].…”

Section: Final Discussion and Conclusion And A Forward Lookmentioning

confidence: 99%

Fibrinaloid Microclots and Atrial Fibrillation

Kell,

Lip,

Pretorius

2024

Biomedicines

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Atrial fibrillation (AF) is a comorbidity of a variety of other chronic, inflammatory diseases for which fibrinaloid microclots are a known accompaniment (and in some cases, a cause, with a mechanistic basis). Clots are, of course, a well-known consequence of atrial fibrillation. We here ask the question whether the fibrinaloid microclots seen in plasma or serum may in fact also be a cause of (or contributor to) the development of AF. We consider known ‘risk factors’ for AF, and in particular, exogenous stimuli such as infection and air pollution by particulates, both of which are known to cause AF. The external accompaniments of both bacterial (lipopolysaccharide and lipoteichoic acids) and viral (SARS-CoV-2 spike protein) infections are known to stimulate fibrinaloid microclots when added in vitro, and fibrinaloid microclots, as with other amyloid proteins, can be cytotoxic, both by inducing hypoxia/reperfusion and by other means. Strokes and thromboembolisms are also common consequences of AF. Consequently, taking a systems approach, we review the considerable evidence in detail, which leads us to suggest that it is likely that microclots may well have an aetiological role in the development of AF. This has significant mechanistic and therapeutic implications.

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Section: Final Discussion and Conclusion And A Forward Lookmentioning

confidence: 99%

Fibrinaloid Microclots and Atrial Fibrillation

Kell,

Lip,

Pretorius

2024

Biomedicines

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The clots removed from ischaemic stroke patients by mechanical thrombectomy are amyloid in nature

Grixti,

Chandran,

Pretorius

et al. 2024

Preprint

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Ischemic stroke due to large vessel occlusion results from the blockage of a major cerebral artery by a clot; however, the origins and molecular composition of these clots remain poorly understood. Mechanical thrombectomy has become a standard treatment to remove obstructive clots, providing a unique opportunity to analyze their properties. We previously demonstrated that blood can clot into an amyloid-like form, generating fibrinaloid microclots (2 to 200 μm) that are highly resistant to fibrinolysis. In this study, archived clots from eight ischemic stroke patients with large vessel occlusion were examined, using samples stored in the Walton Centre Clot Bank in Liverpool, UK. All clots exhibited strong, heterogeneous amyloid staining, revealing a pervasive amyloid component. These findings represent a previously unreported characteristic of stroke clots, highlighting the potential for amyloid-targeted therapies to overcome their fibrinolytic resistance and providing a foundational new insight into ischaemic stroke pathophysiology and treatment.

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The proteome content of blood clots observed under different conditions: successful role in predicting clot amyloid(ogenicity)

Kell,

Pretorius

2024

Preprint

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A recent analysis compared the proteome of (i) blood clots seen in two diseases, viz. sepsis and long COVID, when blood was known to have clotted into an amyloid microclot form (as judged by staining with the fluorogenic amyloid stain thioflavin T) with (ii) that of those non-amyloid clots considered to have formed normally. Such fibrinaloid microclots are also relatively resistant to fibrinolysis. The proteins that the amyloid microclots contained differed markedly both from the soluble proteome of typical plasma and that of normal clots, and also between the disease studies (an acute syndrome in the form of sepsis in an ITU and a chronic disease represented by Long COVID). Many proteins in the amyloid microclots were low in concentration in plasma and were effectively accumulated into the fibres, whereas many other abundant plasma proteins were excluded. The proteins found in the microclots associated with the diseases also tended to be themselves amyloidogenic. We here ask effectively the inverse question. This is: can the clot proteome tell us whether the clots associated with a particular disease contained proteins that are observed uniquely (or are highly over-represented) in known amyloid clots relative to normal clots, and thus were in fact amyloid in nature? The answer is in the affirmative in a variety of major coagulopathies, viz. venous thromboembolism, pulmonary embolism, deep vein thrombosis, various cardiac issues, and ischaemic stroke. Galectin-3-binding protein and thrombospondin-1 seem to be especially widely associated with amyloid-type clots, and the latter has indeed been shown to be incorporated into growing fibrin fibres. These may consequently provide useful biomarkers with a mechanistic basis.

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Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease

Cited by 5 publications

References 315 publications

Fibrinaloid Microclots and Atrial Fibrillation

Fibrinaloid Microclots and Atrial Fibrillation

The clots removed from ischaemic stroke patients by mechanical thrombectomy are amyloid in nature

The proteome content of blood clots observed under different conditions: successful role in predicting clot amyloid(ogenicity)

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